Quantitative, dynamic imaging with Positron Emission Tomography (PET) of N-13 ammonia, C-11 acetate and F-18 deoxyglucose during the past funding period afforded the quantification of regional myocardial blood flow (MBF) and of substrate metabolism in patients early after a myocardial infarction or with chronic coronary artery disease (CAD). Our accomplishments provide further support for the clinical relevance of cardiac PET imaging of MBF and metabolism and offer new insights into the pathophysiology of myocardial ischemia. We believe that additional mechanistic information can be gained only under more controlled conditions in the animal laboratory. Therefore, we wish to refocus the proposed research on the noninvasive assessment of altered vasomotion early in the evolution of CAD as well as in clinically manifest CAD. The hypothesis to be tested is that abnormal coronary vasomotion in preclinical and in clinical CAD can be demonstrated noninvasively with MBF measurements by N-13 ammonia and PET and that beneficial effects of dietary, lifestyle and pharmacologic interventions can be demonstrated noninvasively. We will test our hypothesis by addressing four specific questions: (l) Does short term cardiovascular conditioning improve myocardial flow reserve and vasodilator capacity in CAD patients and what factors are responsible for such improvement? (2) Can preclinical CAD be identified by stress interventions? (3) Can abnormal coronary vasomotion be identified in chronic smokers; is it accentuated in CAD but ameliorated by smoking cessation? (4) Does acute and chronic estrogen administration in postmenopausal women with or at risk for CAD improve abnormal vasomotion and protect against CAD? We will address these questions through accurate and reproducible measurements of regional MBF with N-13 ammonia, dynamic PET and a previously validated tracer kinetic model at rest, during pharmacologically induced hyperemia and stress provocation in normal volunteers, patients with preclinical and overt CAD and postmenopausal women. Serial measurements of MBF during these interventions will be performed prior to and after cardiovascular conditioning, smoking cessation and during chronic estrogen replacement We anticipate that accomplishments of the research objectives will provide a noninvasive tool for the detection of early, preclinical CAD, for demonstrating directly the efficacy of widely advocated interventions as for example regular exercise, lipid lowering diet, lifestyle changes and smoking cessation for delaying or reversing progression of the CAD or even prevention and the protective cardiovascular effects of estrogen replacement in postmenopausal women at risk for CAD.